Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2019.212
Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo
Jongkook Lee1 , Suresh Mandava1 , Sung-Hoon Ahn1 , Myung-Ae Bae2 , Kyung Soo So1 , Ki Sun Kwon1 and Hyun Pyo Kim1,*
1 College of Pharmacy, Kangwon National University, Chuncheon 24341,
2 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
*E-mail: hpkim@kangwon.ac.kr
Tel: +82-33-250-6915, Fax: +82-33-259-5631
Received: December 16, 2019; Revised: April 9, 2020; Accepted: April 22, 2020; Published online: May 11, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
This study aims to develop new potential therapeutic moracin M prodrugs acting on lung inflammatory disorders. Potential moracin M prodrugs (KW01-KW07) were chemically synthesized to obtain potent orally active derivatives, and their pharmacological activities against lung inflammation were, for the first time, examined in vivo using lipopolysaccharide (LPS)-induced acute lung injury model. In addition, the metabolism of KW02 was also investigated using microsomal stability test and pharmacokinetic study in rats. When orally administered, some of these compounds (30 mg/kg) showed higher inhibitory action against LPSinduced lung inflammation in mice compared to moracin M. Of them, 2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)benzofuran-6-yl acetate (KW02) showed potent and dose-dependent inhibitory effect on the same animal model of lung inflammation at 1, 3, and 10 mg/kg. This compound at 10 mg/kg also significantly reduced IL-1β concentration in the bronchoalveolar lavage fluid of the inflamed-lungs. KW02 was rapidly metabolized to 5-(6-hydroxybenzofuran-2-yl)-1,3-phenylene bis(dimethylcarbamate) (KW06) and moracin M when it was incubated with rat serum and liver microsome as expected. When KW02 was administered to rats via intravenous or oral route, KW06 was detected in the serum as a metabolite. Thus, it is concluded that KW02 has potent inhibitory action against LPS-induced lung inflammation. It could behave as a potential prodrug of moracin M to effectively treat lung inflammatory disorders.
Keywords: Arylbenzofuran, 2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)benzofuran-6-yl acetate, Moracin, Prodrug, Airway inflammation, Lung


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